1. Field of the Invention
A method and compositions are for metabolic control of thioretinamide utilization in prevention and treatment of cancer, arteriosclerosis, osteoporosis, dementia, autoimmune disease, and other degenerative diseases of aging. The method combines administration of thioretinamide with enzymatic degradation of homocysteinylated proteins, nucleic acids, and glycosaminoglycans, together with vitamins, amino acids and nitrilosides to enhance metabolic elimination of homocysteine by cystathionine synthase and to promote synthesis of thioretinaco in regenerative cells and measuring and adjusting homocysteine levels to thereby ameliorate the development and progression of degenerative diseases. The compositions include thioretinamide, retinol and combinations thereof with pancreatic enzymes and/or pro-enzymes.
2. Description of Related Art Including Information Disclosed Under 37 CFR 1.97 and 1.98
Abnormal homocysteine metabolism was first implicated in the etiology of degenerative diseases by observation of accelerated arteriosclerosis in children with two different inherited enzymatic disorders resulting from a deficiency of cystathionine synthase and methionine synthase, as reported by McCully K S in American Journal of Pathology 1969; 56:111-128. Accelerated arteriosclerosis was subsequently demonstrated in a child with deficiency of methylene tetrahydrofolate reductase, a third enzymatic disorder of homocysteine metabolism, as reported by Kanwar Y S et al in Pediatric Research 1976; 10:598-609. In all three of these enzymatic disorders, elevation of blood levels of homocysteine is implicated in the pathogenesis of arteriosclerosis by a direct effect of homocysteine on the metabolic activity of arterial cells and tissues.
Abnormal homocysteine thiolactone metabolism was demonstrated in cultures of cells from malignant tissues, as reported by McCully K S in Cancer Research 1976; 36:3198-3202. The results of this study show that cultured malignant cells contain a metabolic blockade of the oxidation of the sulfur atom of homocysteine thiolactone to sulfate, leading to accumulation of homocysteine thiolactone within malignant cells. Homocysteine thiolactone reacts with the free amino groups of macromolecules, forming peptide bonds that cause homocysteinylation of the amino groups of proteins, nucleic acids, and glycosaminoglycans. This metabolic blockade within malignant cells is ascribed to deficiency of a derivative of homocysteine thiolactone that normally occurs within non-malignant cells.
The formation of homocysteine thiolactone from methionine in malignant cells is catalyzed by methionyl t-RNA synthase by an error editing reaction, as reported by Jakubowski H in FEBS Letters 1993; 317:237-240. Abnormal homocysteine thiolactone metabolism in malignant cells is hypothesized to result from a deficiency of or a failure to synthesize an N-substituted derivative of homocysteine thiolactone, as discussed in Cancer Research 1976; 36:3198-3202. According to this hypothesis, normal cells contain a chemopreventive derivative that facilitates sulfate formation from homocysteine thiolactone. The concentration of this hypothetical derivative is believed to be diminished during the carcinogenic transformation of normal to malignant cells through the action of carcinogenic chemicals, radiation, microbes or chronic inflammation. The function of this chemopreventive derivative in normal cells is to prevent accumulation of homocysteine thiolactone by catalyzing its conversion to phosphoadenosine phosphosulfate, sulfate esters of glycosaminoglycans, steroids, and other compounds, and sulfate ions.
Decreased concentration of this chemopreventive derivative in malignant cells leads to the characteristic metabolic abnormalities of malignancy, which are attributable to excessive accumulation of homocysteine thiolactone. According to this concept, the increased growth rate, the aggregation of nucleoproteins, the increased expression of developmentally suppressed genes, the degradation of cellular membranes, and the abnormalities of oxidative metabolism, such as aerobic glycolysis, are attributable to increased accumulation of homocysteine thiolactone within malignant cells. Treatment of animals with transplanted malignant neoplasms by homocysteine thiolactone perchlorate causes increased necrosis within malignant neoplasms, presumably by increased accumulation of homocysteine thiolactone within malignant tissues, as taught in U.S. Pat. No. 4,255,443.
The identity of the N-substituted derivative of homocysteine thiolactone that prevents growth of malignant tumors in animals was elucidated by organic synthesis of anti-neoplastic compounds containing homocysteine thiolactone. Arachidonoyl homocysteine thiolactone amide and pyridoxal homocysteine thiolactone enamine decrease the growth of transplanted murine mammary adenocarcinoma, as reported by McCully K S et al in Chemotherapy 1977; 23:44-49. As taught in U.S. Pat. No. 4,383,994, N-maleyl homocysteine thiolactone amide, N-maleamide homocysteine thiolactone amide, and rhodium trichloride oxalyl homocysteine thiolactone amide suppress the growth of transplanted neoplasms in animals. Encapsulation of N-maleamide homocysteine thiolactone amide within liposomes greatly enhances its anti-neoplastic activity, as reported by McCully K S et al in Proceedings of the Society for Experimental Biology and Medicine 1985; 180:57-61. Structural analysis of these biologically active derivatives of homocysteine thiolactone shows that the hypothetical chemopreventive derivative of homocysteine thiolactone in normal cells is (1) active in a lipid-soluble form, (2) contains a conjugated double bond system with a carbonyl group adjacent to the nitrogen atom of homocysteine thiolactone, and (3) forms a complex with a transition metal atom that enhances anti-neoplastic activity.
U.S. Pat. Nos. 4,618,685 and 4,925,931 teach that the reaction of homocysteine thiolactone with retinoic acid forms N-homocysteine thiolactonyl retinamide (NHTR), known as thioretinamide, and thioretinamide reacts with cobalamin to form N-homocysteine thiolactonyl retinamido cobalamin ((NHTR)2Cbl), known as thioretinaco. Both thioretinamide and thioretinaco have anti-carcinogenic and anti-neoplastic activities, as reported by McCully K S et al in Carcinogenesis 1987; 8:1559-1562 and in Proceedings of the Society for Experimental Biology and Medicine 1989; 191:346-351. The method of synthesis of thioretinamide was significantly improved by use of N-ethyl-N′-β-dimethyl-aminopropyl) carbodiimide in the reaction mixture, as taught in U.S. Pat. Nos. 6,054,595 and 6,287,818. This method replaces the conjugation agent, dicyclohexylcarbodiimide in the reaction mixture of the original method and produces pure thioretinamide in 72% of theoretical yield. This pure thioretinamide and its complex with cobalamin, thioretinaco, have anti-atherogenic activity in rats treated with parenteral homocysteine thiolactone, as reported by Kazimir M et al in Research Communications in Molecular Pathology and Pharmacology 2002; 5,6:179-198.
As taught in U.S. Pat. No. 5,565,558 the anti-carcinogenic, anti-neoplastic, anti-viral, and anti-aging activities of thioretinaco ozonide are enhanced by use of membranergic compositions, specifically the polypeptide cytokines, alpha-interferon, beta-interferon, and gamma-interferon. As taught in U.S. Pat. No. 6,696,082 a therapeutically active composition of thioretinaco ozonide for providing anti-carcinogenic, anti-neoplastic, anti-viral, anti-atherogenic, and anti-aging benefits is formed by thioretinaco ozonide, complexed with adenosine triphosphate and oxygen within an ozone-resistant liposomal carrier.
Studies of homocysteine thiolactone metabolism in the liver of scorbutic guinea pigs that are deprived of dietary ascorbate disclosed a failure of oxidation of homocysteine thiolactone to homocysteine and sulfate, as well as a pathway for synthesis of phosphoadenosine phosphosulfate from the sulfur atom of homocysteine thiolactone, as reported by McCully K S in Nature 1971; 231:391-392. Homocysteic acid, the oxidized sulfonic acid derivative of homocysteine, promotes growth in normal animals and promotes growth and release of insulin-like growth factor, IGF-1, in hypophysectomized animals that are treated with thyroxine, as reported by Clopath P et al in Science 1976; 192:372-374. Young animals and hypophysectomized animals convert more homocysteine thiolactone to homocysteic acid and other oxidized homocysteine derivatives than older or normal animals, as reported by McCully K S in Annals of Clinical and Laboratory Science 1975; 5:147-152. Cultured cells that are deficient in cystathionine synthase and unable to convert homocysteine to cystathionine are able to oxidize the sulfur atom of homocysteine thiolactone to sulfate, demonstrating a pathway for sulfate synthesis that is independent of conversion of homocysteine to cystathionine, cysteine and sulfate, as reported by McCully K S in American Journal of Pathology 1972; 66:83-95. The pathway for synthesis of sulfate from homocysteine thiolactone involves synthesis of thioretinamide from homocysteine thiolactone and retinoic acid and subsequent oxidation of thioretinamide to sulfite, alpha-keto-butyrate and retinoic acid by superoxide, as described by McCully K S in Annals of Clinical and Laboratory Science 1994; 24:27-59.
Nutritional studies have demonstrated that the hyperhomocysteinemia of protein energy malnutrition is associated with reduction in levels of plasma transthyretin, the plasma protein that transports retinol binding protein and thyroxine, as reported by Ingenbleek Y et al in Nutrition 2002; 18:40-46. The metabolic disorder caused by protein energy malnutrition involves decreased synthesis and activity of cystathionine synthase, leading to hyperhomocysteinemia and decreased synthesis of cystathionine and cysteine. Transthyretin contains abundant tryptophan, and the plasma level of transthyretin declines in protein energy malnutrition because of dietary deficiency of tryptophan and other essential amino acids, leading to decreased endogenous synthesis of transthyretin. The heme oxygenase function of cystathionine synthase catalyzes the generation of superoxide radical from dioxygen, as reported by Carballal S et al in Biochemistry 2008; 47:3194-3202. Retinoic acid enhances the stimulation by thyroid hormone of heme oxygenase activity in the liver of thyroidectomized rats, as reported by Smith J J et al in Biochimica Biophysica Acta 1991; 1075:119-122, demonstrating interaction between retinoic acid and the heme group of heme oxygenase. N-(4-hydroxyphenyl)-retinamide, known as fenretinide, induces apoptosis in retinal cells through reactive oxygen species generation and through increased expression of heme oxygenase, as reported by Samuel W et al in Journal of Cellular Physiology 2006; 209:854-865. Investigation of fenretinide demonstrates anti-neoplastic potential, because of its ability to induce apoptosis in malignant cells, as discussed by Hail N Jr et al in Apoptosis 2006; 11:1677-1694, and to increase insulin sensitivity in subjects at risk for breast cancer, as discussed by Johannsson et al in Cancer Research 2008; 68:9512-9518.
The synthesis of thioretinamide from retinol and homocysteine thiolactone by the heme oxygenase function of cystathionine synthase explains the failure of sulfate synthesis from homocysteine thiolactone in experimental scurvy and the function of dehydroascorbate in sulfate synthesis, as reported by McCully K S in Nature 1971; 231:391-392. Thioretinamide is a precursor of thioretinaco by reaction with cobalamin, as taught in U.S. Pat. No. 4,925,931 and reported by McCully K S in Proceedings of the Society for Experimental Biology and Medicine 1989; 191:346-351. Thioretinaco ozonide catalyzes the process of oxygen utilization in oxidative phosphorylation, as reported by McCully K S in Annals of Clinical and Laboratory Science 1994; 24:27-59. The synthesis of thioretinaco from thioretinamide is facilitated by thyroxine that is transported by plasma transthyretin, explaining how oxidative metabolism is stimulated by thyroxine. Only higher eukaryotes contain cystathionine synthase with a heme functional group, and the cystathionine synthase of prokaryotes, such as yeast and flagellates, contains no heme functional group, as discussed by Miles E W et al in Journal of Biological Chemistry 2004; 279:29871-29874. Since embryonic and malignant cells are deficient in the activity of cystathionine synthase, as reported by Kim J et al in Oncology Reports 2009; 21:1449-1454, this formulation explains why malignant cells are deficient in oxidation of homocysteine thiolactone to sulfate by the heme oxygenase function of cystathionine synthase.
The embryologist John Beard discovered that trophoblastic cells of the embryo, which invade the uterine endometrium and myometrium during implantation of the fertilized embryo, are related to the asexual cycle of cellular organisms and are converted to placental cytotrophoblastic and syncytiotrophoblastic cells by the action of lytic enzymes produced by the pancreas of the developing fetus. This discovery is described in his book The Enzymatic Treatment of Cancer and its Scientific Basis, originally published in 1911, and republished by New Spring Press, New York, 2010 with a foreword by Nicholas Gonzalez. Based on the concept that trophoblastic cells, which are distributed within developing tissues of the fetus, are similar in their cellular behavior to malignant cells, Beard introduced the enzyme treatment of cancer. This treatment consists of injecting enzymes and pro-enzymes extracted from porcine pancreas into patients with various forms of primary or metastatic cancer. The trophoblastic theory of the origin of cancer is based on the assumption that adult stem cells are related to the trophoblastic cells which migrate from the yolk sac of the developing embryo into somatic tissues, as described by Beard.
Human fetal and malignant cells produce small quantities of chorionic gonadotrophin, as reported by Acevedo H F et al in Cancer 1995; 76:1467-1475. This hormone is produced in large quantities by the highly malignant tumor of placenta, choriocarcinoma. These observations provide evidence for the trophoblastic origin of malignant cells. Although the origin of adult stem cells in normal human tissues is currently not well understood, the sensitivity of trophoblastic cells to oncolysis by pancreatic enzymes and pro-enzymes forms the theoretical basis for this therapeutic approach, as described by Nicholas Gonzalez and Linda Isaacs in The Trophoblast and the Origins of Cancer, published by New Spring Press, New York, 2009. This sensitivity is related to the accumulation of homocysteinylated enzymes, plasma proteins, and cellular proteins by reaction with excess homocysteine thiolactone that accumulates during aging, atherogenesis, carcinogenesis, and autoimmune diseases, as discussed by Perla-Kajan J et al in Amino Acids 2007; 32:561-572 and by McCully K S in Annals of Clinical and Laboratory Science 1994; 24:27-59.
The enzyme cystathionase (cystathionine γ-lyase) is absent from the liver of human fetus and premature infants, and the activities of the enzymes, cystathionine synthase and adenosyl methionine synthase, are at a level of about 15% to 25% of adult human liver, as reported by Gaull G et al in Pediatric Research 1972; 6:538-547. This discovery shows that the transsulfuration pathway for conversion of homocysteine to cystathionine, cysteine and sulfate is inactive in fetal tissues. Therefore, the pathway for synthesis of sulfate from homocysteine thiolactone, involving synthesis of thioretinamide from retinol and homocysteine thiolactone and subsequent oxidation of thioretinamide to sulfite and sulfate by superoxide, is the source of sulfate groups of glycosaminoglycans utilized in the growth of fetal cells and tissues. The fetal cystathionine synthase assayed in human tissues contains the heme oxygenase function of the enzyme, since sulfate groups of glycosaminoglycans and other molecules are synthesized from the sulfur atom of methionine and homocysteine in embryonic tissues.
In the early 20th century the German biochemist Otto Warburg discovered that embryonic tissues and malignant cells are unable to utilize oxygen for cellular metabolism but instead metabolize glucose to lactate as a source of cellular energy, as summarized in Warburg 0 Science 1956; 123:309-314. In other studies, Warburg showed that carcinogenic chemicals decrease normal cellular respiration by inhibition of oxygenases and by inhibition of transport of electrons by cytochrome enzyme systems. These findings are supported by the demonstration of deficient succinic dehydrogenase and cytochrome oxidase activities within malignant tissues, as reported by Schneider et al in Cancer Research 1943; 3:353-357.
Taken together these early observations can be interpreted as examples of the clonal selection of malignant cells from trophoblastic stem cells that are deficient in the heme oxidase activity of cystathionine synthase. The resulting failure of oxidation of retinol to retinoic acid and failure of reaction of retinoic acid with homocysteine thiolactone to produce thioretinamide by these malignant cells will lead to deficient formation of thioretinaco and failure of oxidative phosphorylation, catalyzed by thioretinaco ozonide, as discussed by McCully K S in Annals of Clinical and Laboratory Science 1994; 24:27-59. The failure of oxidative phosphorylation by malignant cell clones that are deficient in the heme oxygenase function of cystathionine synthase, resulting from decreased production of thioretinaco ozonide from cobalamin and thioretinamide, will lead to an embryonic form of metabolism in which ATP synthesis is dependent upon production of lactate from glucose, otherwise known as aerobic glycolysis.
Nitrilosides are substances containing nitrile groups produced by plants. The most important plant nitriloside is amygdalin (mandelonitrile β-diglucoside), and other nitrilosides are dhurrin (hydroxymandelonitrile β-glucoside), lotaustralin (methylethyl-ketone-cyanohydrin β-glucoside), and linamarin (acetone-cyanohydrin β-glucoside), as discussed in The Nitrilosides in the Prevention and Control of Cancer, the McNaughton Foundation, 1962. Malignant cells contain glucosidase, the enzyme that metabolizes amygdalin and other nitrilosides to cyanide. Normal cells contain rhodanese, a sulfotransferase enzyme that catalyzes thiocyanate synthesis from cyanide and hydrogen sulfide. Malignant cells contain insufficient rodanese to prevent accumulation of cyanide. Therefore, the prevention and control of growth of malignant cells and tissues by dietary nitrilosides are attributable to the consequent accumulation of cyanide within malignant cells. The reaction of cyanide with thioretinaco inactivates thioretinaco ozonide, thereby preventing oxidative phosphorylation, as discussed by McCully K S in Annals of Clinical and Laboratory Science 2009; 39:219-232. This system of chemical surveillance against the growth of trophoblastic malignant cell clones is promoted by dietary or supplemental consumption of amygdalin and other plant nitrilosides.
Hydrogen sulfide is generated from homocysteine by cystathionine synthase and cystathionase, and low levels of hydrogen sulfide decrease oxidative stress and ameliorate pathological conditions such as ischemia-reperfusion injury, hypertension, and renal failure, as reported by Sen U et al in American Journal of Physiology Renal Physiology 2009; 297:F410-F419. Hydrogen sulfide is a key gasotransmitter in sensing oxygen availability in tissues, as discussed by Olson K R in Antioxidants and Redox Signaling 2010; 12:1219-1234. The reducing properties of hydrogen sulfide are responsible for scavenging the reactive oxygen species production induced by increased blood levels of homocysteine, inhibiting myocardial injury, as reported by Chang L et al in Amino Acids 2008; 34:573-585. Increased production of hydrogen sulfide from homocysteine, metabolized from homocysteinylated proteins, nucleic acids, and glycosaminoglycans of apoptotic cells by pancreatic enzymes will promote catabolism of homocysteine and conversion of the sulfur atom of homocysteine to thiocyanate by reaction of hydrogen sulfide with the cyanide generated from dietary nitrilosides.
During the past 42 years since the discovery of the atherogenic properties of homocysteine in 1969, an elevated level of homocysteine has been demonstrated in the plasma of persons with a wide variety of chronic degenerative diseases. A partial list of these conditions includes arteriosclerosis, stroke, acute coronary syndrome, cancer, osteoporosis and fracture, dementia and other neurodegenerative diseases, autoimmune diseases such as lupus erythematosus, ulcerative colitis, thyroiditis, rheumatoid arthritis and pernicious anemia, venous thrombosis and pulmonary embolism, retinal vein thrombosis, hypothyroidism, accelerated aging, renal failure and uremia, diabetes mellitus, metabolic syndrome, macular degeneration, severe psoriasis, organ transplantation with therapeutic immune suppression, protein energy malnutrition, familial or spontaneous amyloidosis, dietary vitamin deficiencies of folate, pyridoxal, and cobalamin, complications of pregnancy such as pre-ecclampsia and placenta previa, and congenital birth defects, including neural tube defects, cleft palate, and congenital heart disease. The etiology of many of these diseases and conditions is incompletely understood. However, many of these chronic degenerative diseases are strongly correlated with the aging process. The importance of deficiencies of thioretinaco ozonide in cells of aging tissues is discussed by McCully K S in Annals of Clinical and Laboratory Science 1994; 24:134-152. Regardless of etiology, however, elevation of plasma homocysteine levels and homocysteinylation of macromolecules in chronic degenerative diseases are susceptible to therapeutic intervention by preservation of cellular oxidative metabolism through increased production of thioretinaco ozonide and by enhanced catabolism of homocysteine produced by enzymatic degradation of homocysteinylated macromolecules. Moreover, preservation of cellular thioretinaco ozonide by membranergic proteins and by the liposomal complex of ATP and oxygen with thioretinaco prolongs survival and counteracts the aging process, as taught in U.S. Pat. Nos. 5,565,558 and 6,696,082.
General aspects of senescence and aging are discussed in Longevity, Senescence, and the Genome by Finch C E, University of Chicago Press, Chicago: 1990, pp 380-385. The synthesis of multiple enzymes of liver, muscle and other organs declines with age, and hormonal factors such as corticosteroid hormones are important in restoration of declining enzyme activity with aging. The absorption of folate, pyridoxal and cobalamin, other vitamins and nutrients declines with aging, correlating with decreased production of gastric acid and intrinsic factor, and decreased formation of pancreatic digestive enzymes with aging.
Increasing evidence supports the role of infectious organisms in the pathogenesis of arteriosclerotic plaques. Remnants of infectious microbes, such as Staphylococcus, Streptococcus, Salmonella, Herpes simplex, Escherichia coli, Chlamydia pneumoniae, Mycoplasma pneumonia, Poryphomonas, other dental organisms, Helicobacter pylori, and Archeae, are detected within plaques by immunohistochemistry, electron microscopy, and hybridization with DNA oligonucleotides directed against microbial nucleic acids. In the case of Chlamydia pneumoniae, live organisms have been cultured from plaques. The lipoproteins of the plasma constitute an innate immune system that is capable of inactivating a wide variety of infectious organisms and their toxins by complexation and aggregation. Homocysteine thiolactone reacts with the free amino groups of the apoB protein of low-density lipoproteins to form aggregates that undergo spontaneous precipitation in vitro, as reported by Naruszewicz et al in Nutrition, Metabolism, and Cardiovascular Disease 1994; 4:70-77. Vulnerable plaques of arteries in atherosclerosis originate from obstruction of vasa vasorum of arterial wall by aggregates formed from lipoproteins complexed with microbial remnants, homocysteinylated lipoproteins, and lipoprotein autoantibodies in areas of high tissue pressure, causing ischemia, degeneration of arterial wall cells and rupture into arterial intima to form a micro-abscess, as described by Ravnskov et al in Annals of Clinical and Laboratory Science 2009; 39:3-16. The obstruction of vasa vasorum by lipoprotein aggregates is exacerbated by swelling and hyperplasia of endothelial cells, as well as by fibrin deposition in the walls of arterioles, as reported by McCully K S in American Journal of Pathology 1969; 56:111-128. These changes in endothelial cell structure and function are manifestations of the endothelial dysfunction caused by hyperhomocysteinemia, as described by McCully K S in Annals of Clinical and Laboratory Science 2009; 39:219-232. Increasing evidence also implicates the presence of microbial remnants within the extracellular amyloid plaques and neurofibrillary tangles within neurons as a factor in the pathogenesis of dementia and neurodegenerative diseases, as described by Fife B, in Stop Alzheimer's Now, Picadilly Books, Colorado Springs Colo., 2011, pp 115-138.
A number of prior art patents have described methods for measuring homocysteine levels in plasma, cerebrospinal fluid, urine and other body fluids such as, for example, Matsuyama, et al. U.S. Pat. No. 6,686,172, Kawasaki, et al. U.S. Pat. No. 6,867,014 and Esaki, et al. U.S. Pat. No. 7,135,306. The prior art has also recognized that high homocysteine levels are markers for various types of disease. Some of the prior art such as Smith, et al. PCT/US97/20021, Dibner, et al. WO 2006/128048 and Horrobin, et al. U.S. Pub. 2005/0147665 provide methods and compositions for reducing homocysteine levels in mammals having elevated levels of homocysteine. Dibner, et al. WO 2006/128048 uses 2-hydroxy, 4-(thiomethyl) butanoic acid for lowering plasma homocysteine; Smith, et al. PCT/US97/20021 uses B vitamins to lower plasma homocysteine and prevent stroke and Horrobin, et al. U.S. Pub. 2005/0147665 uses an agent selected from a group consisting of vitamin B12, folic acid and vitamin B6. This prior art as well as the previously discussed patented prior art of McCully and Kazimir, et al. have not used pancreatic enzymes together with thioretinamide alone or combined with retinol to facilitate the cellular processing of thioretinamide.
The prior art also includes numerous references to the use of retinol and retinoid compositions as topical treatments for skin such as Millstein Pub. US 2010/0113352, Varani U.S. Pat. No. 6,919,072 and Sin, et al. U.S. Pat. No. 7,030,265 as well as for the treatment of diseases associated with aging. For example Roullet, et al. U.S. Pat. No. 6,437,003 uses retinoids for treating high blood pressure and stroke. The retinol prior art has not used retinol with pancreatic enzyme or has combined retinol with enzymes and thioretinamide to employ the heme oxygenase function of cystathionine synthase to facilitate the cellular processing of thioretinamide and the catabolism of homocysteine.